Autophagy is an important cellular process. It is your body’s way of “cleaning house” by degrading and recycling old, broken-down cellular components. Autophagy is also the way cells adapt to metabolic stressors such as nutrient deprivation. It is key in cellular development, cell death, and tumor suppression.
In cancer, autophagy has a dual role. It can both inhibit or promote cancer. Autophagy has a powerful role in the prevention of cancer by stopping cancerous growths. However, for established cancers, autophagy may enable tumor cells to grow and survive.
The role of autophagy in cancer is significantly dependent on context, including the type and stage of the tumor. For this reason, the study of autophagy in cancer is the focus of many researchers. This article will discuss what we are learning about autophagy along with ways to stimulate autophagy for the prevention of cancer.
What is Autophagy?
The term autophagy comes from the Greek words “auto” meaning self and “phagy” meaning eating. It is your intracellular recycling system and cellular self-degradation process where your body cleans out debris and recycles damaged cell components. This leads to the regeneration of cells.
Cells use autophagy to maintain biological function, homeostasis, quality-control of cell contents, and eliminate old proteins and damaged lipids and organelles. Autophagy enables cells to survive external stressors like nutrient deprivation and internal stressors like pathogens.
There are three types of autophagy, macroautophagy, microautophagy, and chaperone-mediated autophagy. The term “autophagy” usually indicates macroautophagy.
Autophagy plays a wide variety of physiological and pathophysiological roles. It consists of several sequential steps:
- Sequestration of organelles and proteins forming an autophagosome (double membrane structure that forms around the pieces of cells that the body has decided to recycle)
- Transport to lysosomes (specialized organelle containing enzymes to degrade proteins)
- Degradation
- Utilization of degradation products.
Cellular stressors stimulate autophagy. These include nutrient deprivation, organelle damage, and abnormal protein accumulation. During nutrient deprivation, autophagy is stimulated to provide proteins and other nutrients for an energy supply, which increases cell survival. Autophagy in stem cells is related to the maintenance of their unique properties, including differentiation and self-renewal.
Dual Roles of Autophagy in Cancer
There are two opposite mechanisms for autophagy in cancer. It is often referred to as a “double-edged sword” because of its dual role in cancer cells.
The role of autophagy in cancer is dynamic and depends in part on the type of tumor and the stage of cancer. Autophagy suppresses tumorigenesis (the production or formation of tumors) by inhibiting cancer-cell survival and inducing cell death. It can constrain tumor initiation by regulating DNA damage and oxidative stress.
On the other hand, autophagy facilitates tumorigenesis by promoting cancer cell proliferation and tumor growth. In established tumors, autophagy can be required for tumor maintenance. Autophagy’s anti-survival or pro-survival effects on cancer cells depends on stimuli, nutrients, and context.
Anti-Cancer Mechanism
Autophagy is generally considered a survival mechanism. It replaces damaged cell components with newly generated functional ones. Autophagy can clean up damaged organelles or protein accumulations and further activate programmed cell death (apoptosis) when the cell is severely damaged. This helps to avoid tumorigenesis.
Pro-Cancer Mechanism
Aberrant autophagy appears to play a central role in cancer. During rapid expansion of a cancer, autophagy can relieve tumor cells from nutrient and oxidative stress. Autophagy is a way that cancer cells can overcome chemotherapeutic drugs and a low energy state.
When tumor cells are deprived of growth/survival factors, this leads to an increase in autophagy that prevents the cells from dying. Autophagy allows tumors to survive environmental stressors and provides intermediates for cell metabolism. When autophagy is prevented under these conditions, the cells undergo apoptosis.
Key Cancer Mechanisms and Autophagy
The four primary pathways in the body for cancer are AMPK, IGF-1, mTOR, and the p53 gene. It is important to understand these key cancer mechanisms and how they are linked to autophagy.
1 | AMPK
AMPK (Adenosine Monophosphate-activated Protein Kinase) is an energy regulating molecule that signals ATP production. It is the energy switch that controls cell growth and several other cellular processes, including autophagy.
As ATP is broken down for energy within cells, phosphate groups are removed to form ADP (Adenosine Diphosphate) and AMP (Adenosine Monophosphate). When the ratio of AMP to ATP is increased, this is a sign that energy is getting low. AMPK is activated and signals the upregulation of ATP production.
AMPK activity can be upregulated with carbohydrate restriction and numerous plant-based compounds. Upregulation of the AMPK pathway helps the body fight cancer by diverting sugar from cancer cells to healthy cells. This limits the fuel supply to cancer cells.
2 | IGF-1
IGF-1 (insulin-like growth factor) is a growth-stimulating hormone that regulates the reproduction and regeneration of cells. It has been reported to regulate cell survival, proliferation, differentiation, and metabolism. IGF-1 has an inhibitory role on autophagy in certain cancer cells.
3 | mTOR
mTOR (mammalian target of rapamycin) is a physiological pathway that regulates cell growth and replication and is necessary for a healthy body. mTOR is a key autophagy regulator integrating amino acid starvation, growth factor deprivation, the drop of ATP or oxygen levels and accumulation of reactive oxygen species to the autophagy pathway activities. However, cancerous tissues have an elevated activation of the mTOR pathway. This can contribute to the rapid cell division found in cancer.
4 | The p53 Gene
There is an important relationship between autophagy and the p53 gene. The p53 gene regulates what happens to damaged DNA sequences before they lead to problems in cell development.
When functioning properly, the p53 gene responds in two ways to disorderly cells. If the defective DNA can be repaired, the p53 gene allows the cell to go back into its normal cycle of growth and reproduction. If the defective DNA cannot be repaired, the p53 signals for cellular apoptosis (programmed cell death), halting the potential for cancerous growth. In this way, the p53 gene has a protective function by activating autophagy.
Autophagy also suppresses the p53 gene. The suppression of p53 by autophagy is important for tumor promotion. Additionally, high levels of oxidative stress block the p53 gene that governs cellular apoptosis. When this happens, our bodies can no longer regulate cell division and cancers can develop.
Autophagy, Mitophagy, Apoptosis and Cellular Senescence
Autophagy is one of the biological processes that control cell death and survival. Mitophagy, apoptosis and cellular senescence are additional processes. It is important to look at the relationship of each of these processes to autophagy.
Mitophagy
Mitophagy is a selective form of autophagy involving the recycling of mitochondria, the powerhouse of your cells. (9) Mitophagy ensures the preservation of healthy mitochondria through the removal of damaged or superfluous mitochondria.
Like autophagy, mitophagy has a dual role in cancer. The function of both mitophagy and autophagy depends on cancer development, progression, and type. They can act to promote cancer progression by helping cancer cells to survive stress.
When mutated or abnormal, mitophagy and autophagy can induce carcinogenesis by influencing cell signaling or promoting intracellular toxicity. Cancer stem cells are usually characterized by a dysregulation of autophagy/mitophagy.
Apoptosis
Autophagy and apoptosis both play critical roles in controlling cell death and survival. Apoptosis is the process of programmed cell death. Cells are programmed to die when their useful life is done. This process is essential in maintaining good health.
Apoptosis causes a lot of metabolic waste which induces inflammation and puts stress on the body. Unlike apoptosis, autophagy is a very clean and energy efficient process.
In response to stress or damage, autophagy is stimulated to shut down the anabolic processes to keep cells viable and metabolically inert. This allows for cellular repair and prevents further damage. The more cells that can repair themselves, the less inflammation and metabolic waste that is produced.
When cellular damage is too severe, apoptosis kicks in to eliminate irreparable cells to maintain tissue homeostasis. Cellular apoptosis is basically the body’s backup mechanism for eliminating diseased cells.
Cellular Senescence
Another critical stress response process in the body is cellular senescence. Cellular senescence prevents the proliferation of damaged cells, acting as a potent tumor suppressive mechanism.
Autophagy can suppress cellular senescence. It alleviates stressors that can cause cellular senescence such as dysfunctional mitochondria and oxidative stress. Autophagy also maintains the lysosomal integrity of the cell, acting as an anti-senescence mechanism.
However, there is a complex causal relationship between cellular senescence and autophagy. It appears that autophagy has a dual role in cellular senescence. General autophagy under normal conditions can promote senescence while selective autophagy may act to prevent senescence.
Click here for our top 10 ways to jumpstart autophagy for cancer protection!
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